Antihistaminic and motion sickness preventing compositions



United States Patent O ce Patented ,jfjj fif,

1 2 3,422,195 1962 n, 852) and makes it necessary that the drug beANTIHISTAMINIC AND MOTION SICKNESS tlallfen rather llong btefore thebeginning of the journey. PREVENTING COMPOSITIONS is can cast y beorgotten because of the excitement Gerrit Alberda, Amsterdam,Netherlands, assignor, by Preceding the depat'tuw mesn i t t A c F (A td Ch i 5 On the other hand, drugs lacking this drawback often ljarmacie)N.V., Amsterdam, Netherlands, a limitedhave the disadvantage of a shortlasting action, so that liability company of the Netherlands they mustbe taken frequently. This is inconvenient, es- No Drawing. Filed Sept.22, 1964, Ser. No. 398,441 pecially on angjoumey Clams gg g g pig g gf k1963 Now, with regard to their antimotion sickness properus. Cl. ep 3Claims 10 ties, it has been found that the new compositions according tothe invention have none of the disadvantages men- Int. Cl. A61k 25/00;C07d 51/00 tioned before. On the contrary, their onset of action is Thisinvention relates to new antihistaminic motion very fast, whereas theprotection Obtained lasts for sickness preventing compositions. severalhours. Some results obtained with preparations It 18 known thatcinnarizine (l-cinnamyl-4- n hybased on mixtures according to theinvention, especially drylpiperazine) and its acid addition saltspossess a strong regarding their influence on the labyrinth, will bepubantihistaminic activity (for example, as indicated in fi h d h tl bW, J, Oo t m Briti h P tent 309,760, P i ularly with respectto com-Recapitulating, it is an object of the invention to propound 60f thetable therein). cure new, potentiating antihistaminic compositions, and

It is also known that oyclizine and chloroyolizine and 20 another objectis to procure compositions having a fast their physiologicallyacceptable acid addition salts, onset of action as well as a longlasting action in preventexample, l -(4-chlorobenzhydryl)-4- y P P ingmotion sickness. A further object can be seen in the hydfoohlol'ldoMerck Index, 7th 'a 1960, P g method of preventing motion sickness byusing preparacan be used as antihistaminic agents. tions containing thenew compositions.

By experiments with the above mentioned antihis- The last-mentionedpreparations can be prepared by taminics, it has been found surprisinglythat mixtures of mixing the compositions according to the invention withcinnarizine and/or its physiologically acceptable acid suitablepharmaceutical carriers such as lactose, amylum, addition salts withcyclizine, and/or chlorcyclizine, and/ talc, magnesium stearate, and thelike, and making up their physiologically acceptable acid addition saltsthe resulting mixture into tablets, pills, powders, potions possess muchstronger antihistaminic activity than would d th like ooo p from moreaddition of the individual The following examples only serve toillustrate the tlvltles of the components methods by which thecompositions and preparations ac- The amount o component Present 111 themixture cording to the invention can be obtained but are not to n beVaried Within Wide ranges but, p h y, from be construed as limiting theinvention to the particular about 10 to about y Welght, of the mlxturoof methods or the particular compounds specifically desaid substances.ib d,

In the following table some results are listed showing E l 1 thepotentiating effect of mixtures according to the invention. Theantihistaminic activity was measured in guinea pigs with the methoddescribed by E. G. van cordmg to the Invention 5 grams of l'cmnamyl'tiProosdij-Hartzema et al., Acta Physiol. Pharmacol. Neerl.benzhydrylpiperazine i intimately mixed with 5 grams 8, 339 340 (1959)of 1-d1phneyl-4-methylp1perazine lactate.

For the preparation of a potentiating composition ac- Percentages ofguinea pigs protected against the in- Example 2 fiuence of histamine atvarious intervals after oral ad- I ministration of the compounds andcompositions in- In a mortar, 8 grams of1-cinnamyl-4-benzhydrilpiperdicated: azine dihydrochloride is rubbeddown and thereupon TABLE 7 Dose Percentage of animals protected after-Administered compounds 1 in mgJkg. t 15 min. 30 min. 1 hour 2 hours 4hours 24 hours Clnnarizine 5 0 (l 0 Cinnarizine 10 20 80 60 cyclizine-.-5 0 Chlorcyclizin 5 10 90 60 0 0 Cinnarizine 5 plus 80 100 100 Cyelizine5 Ciunarizine 5 plus 60 100 100 100 100 100 Chlorcyelizine 5 i In theseexperiments, cinnarizine and ehlorcyclizine were both administered asthe hydrochlorldes, whereas cyclizine was given as the lactate.

2 Expressed in milligrams of the free base.

It is known from several publications that some antimixed thoroughlywith 8 grams of ground l-(4-chlorohistaminics can also he used inpreventing motion sickbcnzhydril)-4-methylpiperazine dihydrochloride. Tothe ness (for example, as in L. N. Gay et al., The Prevenmixture areadded 144 grams of lactose and mixing is contion and Treatment of MotionSickness, Bull. John Hoptinned until it is homogeneous. The compositionis divided kins Hosp., 1949, 84, 470), and the new compositions intopowders of 0.5 gram each, which can be used directly according to theinvention were further examined as to by oral administration. theirantimotion sickness properties.

One of the most important disadvantages of several known drugs used inthe prevention of motion sickness For the preparation of tablets usefulin preventing is their delayed onset of action. This retardationsomemotion sickness, 1.25 grams of cinnarizine, 2.5 grams of timesamounts to two or more hours (see Brit. Med. J., chlorcyclizinehydrochloride (or cyclizine lactate), 4.75

Example 3 grams of lactose, 2.5 grams of maize flour, 0.25 gram of talc,0.15 gram of magnesium stearate and 0.1 gram of sunset yellow areintimately mixed and made up into 100 tablets which can be orallyadministered.

The above formula is a preferred preparation. However, the proportion ofthe active components can be varied widely. The only condition is thateach component is present in a potentiating amount to give a fasteronset of action and/or an increased duration of activity to thecomposition.

What is claimed is:

1. Antihistaminic and motion sickness preventing composition containing,as its essential active ingredients, a first compound selected from thegroup consisting of cinnarizine and its physiologically acceptable acidaddition salts, in combination with a second compound selected from thegroup consisting of cyclizine, chlorcyclizine and their physiologicallyacceptable acid addition salts, the by weight ratio of said firstcompound to said second compound being in the range from 1:1 to 1:2.

2. Antihistaminic and motion sickness preventing composition as in claim1; in which said first and second compounds are present as an intimatemixture in the composition.

3. The method of preventing motion sickness in humans and animals byorally administering to a being susceptible to motion sicknesstherapeutically effective amounts of a composition containing, as itsessential active ingredients, a first compound selected from the groupconsisting of cinnarizine and its physiologically acceptable acidaddition salts, in combination with a second compound selected from thegroup consisting of cyclizine, chlorcyclizine and their physiologicallyacceptable acid addition salts, the by Weight ratio of said firstcompound to said second compound being in the range from 1:1 to 1:2.

Merck Index, 7th ed., published by Merck and C0,, Inc., Rahway, N.J.,1960, pp. 236, 308 and 309.

RICHARD L. HUFF, Primary Examiner.

1. ANTIHISTAMINIC AND MOTION SICKNESS PREVENTING COMPOSITION CONTAINING,AS ITS ESSENTIAL ACTIVE INGREDIENTS, A FIRST COMPOUND SELECTED FROM THEGROUP CONSISTING OF CINNARIZINE AND ITS PHYSIOLOGICALLY ACEPTABLE ACIDADDITION SALTS, IN COMBINATION WITH A SECOND COMPOUND SELECTED FROM THEGROUP CONSISTING OF CYCLIZINE, CHLORCYCLIZINE AND THEIR PHYSIOLOGICALLYACCEPTABLE ACID ADDITION SALTS, THE BY WEIGHT RATIO OF SAID FIRSTCOMPOUND TO SAID SECOND COMPOUND BEING IN THE RANGE FROM 1:1 TO 1:2.